U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy

被引:106
作者
Hatakeyama, S
Matsumoto, M
Kamura, T
Murayama, M
Chui, DH
Planel, E
Takahashi, R
Nakayama, KI
Takashima, A [1 ]
机构
[1] RIKEN, Brain Sci Inst, Lab Alzheimers Dis, Saitama 3510198, Japan
[2] RIKEN, Brain Sci Inst, Lab Motor Syst Neurodegenerat, Saitama, Japan
[3] Kyushu Univ, Med Inst Bioregulat, Dept Mol & Cellular Biol, Fukuoka 812, Japan
[4] Kyushu Univ, Med Inst Bioregulat, Dept Mol Genet, Fukuoka 812, Japan
[5] Japan Sci & Technol Corp, CREST, Saitama, Japan
关键词
carboxyl terminus of Hsc70-interacting protein; neurodegeneration; neurofibrillary tangle; tau; ubiquitylation;
D O I
10.1111/j.1471-4159.2004.02713.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated and ubiquitylated tau, are exhibited at regions where neuronal loss occurs in neurodegenerative diseases; however, the mechanisms of NFT formation remain unknown. Molecular studies of frontotemporal dementia with parkinsonism-17 demonstrated that increasing the ratio of tau with exon 10 insertion induced fibrillar tau accumulation. Here, we show that carboxyl terminus of Hsc70-interacting protein (CHIP), a U-box protein, recognizes the microtubule-binding repeat region of tau and preferentially ubiquitylates four-repeat tau compared with three-repeat tau. Overexpression of CHIP induced the prompt degradation of tau, reduced the formation of detergent-insoluble tau and inhibited proteasome inhibitor-induced cell death. NFT bearing neurons in progressive supranuclear palsy, in which four-repeat tau is a component, showed the accumulation of CHIP. Thus, CHIP is a ubiquitin ligase for four-repeat tau and maintains neuronal survival by regulating the quality control of tau in neurons.
引用
收藏
页码:299 / 307
页数:9
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